Research project

RESTORING T-CELL HOMEOSTASIS BY IN VIVO MANIPULATION OF DENDRITIC CELLS

The loss of T-cell homeostasis and tolerance towards self-antigens is the underlying cause of autoimmune and inflammatory diseases like atherosclerosis, rheumatoid arthritis or type I diabetes. Traditionally, the treatment of these diseases consisted on systemic immune suppression, which can entail serious adverse effects, therefore a more target approach is required. T regulatory cells (Tregs) have the ability to control these exacerbated reactions towards self-antigens by suppressing the activity of effector T cells. The natural pathway for the acquisition of peripheral tolerance is mediated by antigen-presenting cells such as dendritic cells (DCs). Especially tolerogenic DCs (TolDCs), which present a semi-mature phenotype, characterized by the down-regulation of co-stimulatory molecules such as CD86 and CD80, have the ability to induce Tregs-mediated tolerance. Ex vivo generation of tolDCs and their subsequent administration as a cell-based therapy has demonstrated to reduce the pro-inflammatory responses in experimental models of inflammatory disease. However, this approach presents considerable challenges for its translation to clinic, such as the complex manufacture and high costs. The use of vaccines to induce tolDCs in vivo is a more broadly applicable and translational approach. Certain nanoparticulate carrier systems, such as specific liposomal formulations, can target antigen-presenting cells and induce a tolerogenic phenotype. As we showed in a previous report, anionic liposomes containing 1,2-distearoyl-sn-glycero-3-phosphoglycerol (DSPG) can induce tolerogenic DCs and Tregs in a mouse model of atherosclerosis, leading to significant reduction of atherosclerosis. We aim to expand their application and increase the tolerogenic capacity of these nanoparticles by developing new formulations containing tolerogenic adjuvants, such as rapamycin or vitamin D, and antigens that are important in the pathogenesis of autoimmune diseases, such as type I diabetes or rheumatoid arthritis.